EP0602814A1 - Kristallformen von optisch aktiven Isoindolinen und ihre Anwendung - Google Patents

Kristallformen von optisch aktiven Isoindolinen und ihre Anwendung Download PDF

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Publication number
EP0602814A1
EP0602814A1 EP93309487A EP93309487A EP0602814A1 EP 0602814 A1 EP0602814 A1 EP 0602814A1 EP 93309487 A EP93309487 A EP 93309487A EP 93309487 A EP93309487 A EP 93309487A EP 0602814 A1 EP0602814 A1 EP 0602814A1
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EP
European Patent Office
Prior art keywords
crystal
chloro
naphthylidin
carbonylmethyl
isoindolin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93309487A
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English (en)
French (fr)
Inventor
Giichi Goto
Naohisa Fukuda
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Filing date
Publication date
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Publication of EP0602814A1 publication Critical patent/EP0602814A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the present invention relates to a pharmaceutical, specifically a crystallized optically active isoindoline derivative effective in the improvement, treatment or prevention of anxiety-associated nervous symptoms, and an intermediate for synthesis thereof.
  • Antianxiety drugs which act on the central nervous system, new compounds having no benzodiazepine skeleton have been investigated. Antianxiety and other drugs acting on the central nervous system must be orally administrable and cause no side effects such as muscular relaxation or sleep induction.
  • the present inventors conducted investigations and discovered an isoindolinone derivative represented by Formula A, which exhibits excellent antianxiety action, and a pharmacologically acceptable salt thereof (see Japanese Patent Publication Open to Public Inspection No. 69773/1986).
  • X represents hydrogen, halogen or nitro
  • Ar represents phenyl or naphthyridinyl which may be replaced with a substituent; with respect to Z1 and Z2, either represents hydrogen while the other represents a lower alkanoyloxy or hydroxy, or both represent a lower alkoxy, or both cooperatively represent hydroxyimino, oxo or a group represented by the formula: wherein Y represents oxygen or sulfur; A represents a lower alkylene chain which may be branched.
  • the compounds of the above formulae (II), (III) and (IV) each have asymmetric carbon atoms in their molecular structure involving two optical isomers,
  • optically active isoindolinone derivatives form several polymorphs.
  • Figure 1 shows the results of high performance liquid chromatography obtained in the Analytical Example (the racemic compound of the compound of Example 1 used), in which peaks 1 and 2 are for (S)-(+) configuration and (R)-(-) configuration, respectively.
  • Figure 2 shows the results of high performance liquid chromatography obtained in the Analytical Example (the compound of Example 1 used), in which peak 1 is the peak for (S)-(+) configuration.
  • an optically active isoindoline derivative represented by the following formula (I') exhibits excellent antianxiety action, i.e., improving, therapeutic and preventive action on anxiety-associated nervous symptoms, and that the (S)-( + )-isoindoline derivative alone possesses bioactivities, while the (R)-(-) configuration has no bioactivity, the latter being the first such discovery in the field of antianxiety drugs.
  • the inventors conducted further investigations based on these findings, and developed the present invention.
  • the present invention comprises a crystallized optically active isoindoline derivative represented by the formula: wherein X represents halogen, -OH, or its reactive derivative and an improving, therapeutic and preventive agent for anxiety-associated nervous symptoms whose active ingredient is an (S)-(+)-isoindoline derivative represented by the formula: wherein X' represents
  • the present invention further provides the crystal forms of (S)-(+)-2-(7-chloro-1,8-naphthylidin-2-yl)-3-[(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)carbonylmethyl]isoindolin-1-one, which is shown by formula (I'; X' is designated by A-form, B-form, C-form, D-form and E-form crystals.
  • the compound having halogen or -OH for X is useful as an intermediate for synthesis of a compound wherein X is
  • halogen represented by X in the Formula (I) examples include fluorine, chlorine, bromine, iodine, with preference given to chlorine.
  • the (S)-(+)-isoindoline derivative of the present invention is a compound represented by the following formula (V): wherein X represents halogen, -OH,
  • the bioactive compound of the present invention can be represented by the following formulae (VI, VII and VIII).
  • the optically active isoindoline derivatives form several polymorphs.
  • (S)-(+)-2-(7-chloro-1,8-naphylidin-2-yl)-3-[(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)carbonylmethyl]isoindolin-1-one shown by the compound (VI) above has 5 crystal forms of A-form to E-form shown by the following the Distance Values ( ⁇ : approximate value) by a powder x-ray diffraction.
  • These crystal forms may be further used as a mixture of two or more of the A- to E-forms for a pharmaceutical composition.
  • B-form crystal is stable among the crystal forms and is usable as a medicine.
  • the optically active (S)-(+)-isoindoline derivative (V), a compound of the present invention can be obtained by resolving the racemic compound isoindoline-3-acetate intermediate (IX) by a known method to yield an optically active (S)-(+)-isoindoline-3-acetate intermediate (X), and subsequently amidating the compound (X) by a known method (e.g., the method described in Japanese Patent Publication Open to Public Inspection No. 69773/1986).
  • the racemic compound isoindoline-3-acetate intermediate (IX) can be synthesized by the method described in Japanese Patent Publication Open to Public Inspection No. 69773/1986. It can be optically resolved by the typical methods described below.
  • the respective crystal forms of (S)-(+)-2-(7-chloro-1,8-naphthylidin-2-yl)-3-[(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)carbonylmethyl]isoindolin-1-one shown by formula (VI) may be produced directly from a reaction mixture during a purification process, or may be produced by converting physically or physico-chemically another crystal form or other crystal forms under a control of recrystalizing condition, such as solvent, temperature and drying process, to a desired crystal form.
  • *ROH represents an optically active alcohol.
  • optically active alcohols preferred for this method include 1-menthol and (+)- or (-)- ⁇ -methylbenzyl alcohol.
  • optically active isoindoline derivative of the present invention can also be produced by resolving the racemic compound thereof using a chiral column.
  • Capability of specific binding to a benzodiazepin receptor was determined in accordance with the method described in the literature [Nature, 266 , 732 (1977); European J. Pharmacol., 48 , 263 (1978)]. Specifically, a crude mitochondrial fraction obtained from the cerebral cortex of male SD rats at 9 to 10 weeks of age was suspended in 50 mM Tris-HCL buffer (pH 7.4), and incubated, together with several concentrations of the subject drug and 3H-diazepam (final concentration 2 nM), at 4 °C for 20 minutes. This suspension was then filtered through a Whatman GF/B glass fiber filter, and the 3H-diazepam radioactivity on the filter was measured using a liquid scintillation counter. The concentration of the subject drug at which 3H-diazepam binding was inhibited by 50% was taken as the IC50 value.
  • Example 1 had no enhanced affinity to the benzodiazepin receptor, because the racemic compound itself already possesses nearly fully potent action.
  • the antianxiety action of the compound of the present invention was investigated.
  • Antianxiety action was assessed, in accordance with the method of Vogel et al. [Psychopharmacologia, 21 , 1 (1970)], as follows. An apparatus, comprising a large transparent box with a stainless steel lattice floor and a small dark opaque box with a water drinking port, was set so that the subject animals' feet were electrically stimulated via the lattice floor once per 20 times of water drinking. Male rats (SD/JCL), denied water for 48 hours, were orally dosed with the subject compound. 30 minutes later, each animal was placed in the apparatus; water drinking frequency in 3 minutes was counted, and the rate of increase from the water drinking frequency in the physiological saline dosed group was calculated for an index of intensity of antianxiety action to determine the minimum effective dose.
  • Compound (VI), typical among the compounds (V) of the present invention, and the racemic compound thereof were compared as to antianxiety action.
  • the results are shown in Table 2.
  • Antianxiety action Compound in Example 1 1.25 mg/kg, p.o. 10 mg/kg, p.o. Antianxiety action (Vogel method) Compound in Example 3 5.0 mg/kg, i.p. 20 mg/kg, i.p.
  • Compound (V) of the present invention acts on the central nervous system of mammals. It possesses a high capability of specific binding to benzodiazepine receptors and exhibits strong antianxiety action in anticonflict experiments in rats.
  • the minimum lethal dose (MLD) of the compound of the present invention in rats is over 1000 mg/kg (P.O.), much higher than the minimum effective dose (MED), indicating a very wide range of drug safety.
  • the MED of compound (in Example 1) for antianxiety action in rats is 1.25 mg/kg (P.O.) or lower.
  • Compound (V) of the present invention in comparison with the racemic isoindolinone derivative described above and the currently commercially available antianxiety benzodiazepin drugs, has a wider range of drug safety, separation of action from hypnotic action, muscular relaxation action and other side effects is very good, the sleepiness, dizziness and similar side effects are very slight, and its oral administration offers a marked effect; it is useful as an antianxiety drug in humans and other mammalians.
  • Diseases against which the compound of the present invention is effective include various psychosomatic diseases and anxiety syndromes, such as autonomic imbalance, nervous vomiting, nervous dermatitis, alopecia areata, nervous angina pectoris and nervous dyspnea; the compound of the present invention can be used to prevent or treat these diseases.
  • the compound of the present invention also exhibits antispasmodic action. It can therefore also be used to treat epilepsy and traumatic spasm, for instance.
  • the compound of the present invention is, for example, administered to humans and other mammalians orally or parenterally in various dosage forms, including tablets, granules, capsules, injections and suppositories.
  • dose quantity varies depending on the target disease, symptoms and other factors, it is normally 0.01 mg to 100 mg, preferably 0.05 mg to 10 mg daily in oral administration for adults.
  • the powder X-ray diffractions in Examples were measured by use of the model of Rigaku RINT System and Cu ⁇ Ka as X-ray source at the condition of 40KV and 40mA.
  • Example 1 B-form crystal of (S)-(+)-2-(7-chloro-1,8-naphthylidin-2-yl)-3-[(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)carbonylmethyl]isoindolin-1-one
  • the precipitated tabular crystals were collected by filtration and washed with a small amount of acetone.
  • the mother liquor and the washings were combined and heated to concentrate.
  • the resulting oily substance was dissolved in 60 ml of acetone with heating, and the resulting solution was kept standing at room temperature.
  • the precipitated needle crystals were collected by filtration and washed with a small amount of acetone.
  • Example 1 (1) (R)-(+)-2-(7-chloro-1,8-naphthylidin-2-yl)-1-oxoisoindolin-3-acetic acid ⁇ (+)-cinchonine salt
  • the former tabular crystals obtained in Example 1 (1) were recrystallized from methanol-acetone (1:3) to yield 4.1 g of a pure (R)-(+) salt.
  • Example 1 The compound of Example 1, typical among the compounds of the present invention, and the racemic modification thereof, were analyzed by high performance liquid chromatography using an optical resolution column. Analytical conditions Column Chiral Cell OJ (4.6 ⁇ 250 mm) Mobile phase n-hexane-2-propanol-ethanol (10: 1: 1, v/v) Flow rate 1 ml/min Detection UV 344 nm
  • the crystals thus obtained were identified as those of monohydrate by subjecting them to determination by means of thermobalance and powder X-ray.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP93309487A 1992-12-18 1993-11-29 Kristallformen von optisch aktiven Isoindolinen und ihre Anwendung Withdrawn EP0602814A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP33899492 1992-12-18
JP338994/92 1992-12-18

Publications (1)

Publication Number Publication Date
EP0602814A1 true EP0602814A1 (de) 1994-06-22

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EP93309487A Withdrawn EP0602814A1 (de) 1992-12-18 1993-11-29 Kristallformen von optisch aktiven Isoindolinen und ihre Anwendung

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EP (1) EP0602814A1 (de)
CA (1) CA2111031A1 (de)
FI (1) FI935687A7 (de)
NO (1) NO934375L (de)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076995A1 (fr) * 1999-06-14 2000-12-21 Mitsubishi Pharma Corporation Procede de preparation de derives de l'acide (-)-1,4-benzothiazine-2-acetique
US7968570B2 (en) 2004-08-13 2011-06-28 Astrazeneca Ab Isoindolone compounds and their use as metabotropic glutamate receptor potentiators
US8148372B2 (en) 2008-06-06 2012-04-03 Astrazeneca Ab Metabotropic glutamate receptor isoxazole ligands and their use as potentiators—286
US8153638B2 (en) 2005-08-12 2012-04-10 Astrazeneca Ab Metabotropic glutamate-receptor-potentiating isoindolones
US8377939B2 (en) 2007-06-07 2013-02-19 Astrazeneca Ab Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators 842

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0174858A1 (de) * 1984-09-14 1986-03-19 Takeda Chemical Industries, Ltd. Isoindolinonderivate, ihre Herstellung und Verwendung
EP0529778A1 (de) * 1991-07-10 1993-03-03 Takeda Chemical Industries, Ltd. Optisch aktive Isoindolin-Derivate, ihre Herstellung und Anwendung

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0174858A1 (de) * 1984-09-14 1986-03-19 Takeda Chemical Industries, Ltd. Isoindolinonderivate, ihre Herstellung und Verwendung
JPS6169773A (ja) * 1984-09-14 1986-04-10 Takeda Chem Ind Ltd イソインドリノン誘導体
EP0529778A1 (de) * 1991-07-10 1993-03-03 Takeda Chemical Industries, Ltd. Optisch aktive Isoindolin-Derivate, ihre Herstellung und Anwendung

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076995A1 (fr) * 1999-06-14 2000-12-21 Mitsubishi Pharma Corporation Procede de preparation de derives de l'acide (-)-1,4-benzothiazine-2-acetique
US7968570B2 (en) 2004-08-13 2011-06-28 Astrazeneca Ab Isoindolone compounds and their use as metabotropic glutamate receptor potentiators
US8153638B2 (en) 2005-08-12 2012-04-10 Astrazeneca Ab Metabotropic glutamate-receptor-potentiating isoindolones
US8377939B2 (en) 2007-06-07 2013-02-19 Astrazeneca Ab Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators 842
US8377940B2 (en) 2007-06-07 2013-02-19 Astrazeneca Ab Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators—842
US8148372B2 (en) 2008-06-06 2012-04-03 Astrazeneca Ab Metabotropic glutamate receptor isoxazole ligands and their use as potentiators—286

Also Published As

Publication number Publication date
FI935687A0 (fi) 1993-12-17
NO934375L (no) 1994-06-20
FI935687L (fi) 1994-06-19
CA2111031A1 (en) 1994-06-19
NO934375D0 (no) 1993-12-02
FI935687A7 (fi) 1994-06-19

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